The Raf/MEK/ERK pathway is critical for cell survival, growth, proliferation and tumorigenesis. See, e.g., Nanxin Li, et al., Current Opinion in Investigational Drugs. Vol. 8, No. 6 (2007): 452-456. Raf kinases exist as three isoforms, A-Raf, B-Raf and C-Raf. Among the three isoforms, studies have shown that B-Raf functions as the primary MEK activator. B-Raf is one of the most frequently mutated genes in human cancers. B-Raf kinase represents an excellent target for anticancer therapy based on preclinical target validation, epidemiology and drugability.
Angiogenesis, the process of blood vessel formation and growth, has been recognized as important in tumor pathophysiology and a suitable target for anti-cancer therapy VEGF is the primary mediator of both normal and tumor-associated angiogenesis through increased microvascular permeability to plasma proteins (see, e.g., D. J. Hicklin et al., J. Clin. Oncol. (2005) 23(5): 1011-1027), induction of endothelial cell division and migration (see, e.g., H. F. Dvorak et al., Am. J. Pathol., (1995) 146(5):1029-1039, 3; N. Ferrara et al., Endocr. Rev. (1997) 18(1):4-25), promotion of endothelial cell survival through protection from apoptosis (see, e.g., L. E. Benjamin et al., J. Clin. Invest. (1999) 103(2): 159-165; R. K. Jain et al., Proc. Natl. Acad. Sci. USA, (1998) 95(18):10820-10825) and reversal of endothelial cell senescence (see, e.g., Y. Watanabe et al., Oncogene (1997) 14(17):2025-2032). VEGF exerts its biological effect through interaction with receptors (VEGF receptors 1, 2 and 3) present on the endothelial cell surface. Upon binding of VEGF to the extracellular domain of its receptor, dimerisation and autophosphorylation of the intracellular receptor tyrosine kinase occurs and a cascade of downstream proteins are activated. Another protein relevant to tumor angiogenesis is platelet derived growth factor (PDGF). The receptor for the PDGF protein is expressed on pericytes, smooth muscle cells and capillary endothelial cells. PDGF exerts its biological effect through engagement of receptor on these vascular supporting cells, affecting processes relevant to tumour angiogenesis, including endothelial cell motility and apoptosis (see, e.g., C. H. Heldin et al., Biochim. Biophys. Acta (1998) 1378(1):F79-F113).
Small molecule multi-kinase inhibitors are being developed for anticancer therapy. Certain urea derivatives, which target multi-kinase including B-Raf, VRGF and PDGF, have been developed for anticancer therapy (see, e.g., WO2000042012). Inhibitors of other chemotype have also been disclosed in, e.g., US 2006/0189627, US 2006/0281751, US 2007/0049603, WO 2007/002325, WO 2007/002433, and WO2009/111279.
Pentafluorosulfanyl group is a relatively novel group in organic chemistry and it has not been found in any existing approved drugs. The present invention relates to a class of novel pentafluorosulpholane-substituted urea derivatives as multi-kinase inhibitors which targets kinases including B-Raf, VRGF and PDGF. These novel multi-kinase inhibitors also exhibit unique cycotoxicity profiles that are different from the known inhibitors. Accordingly, the compounds of the invention are useful in the treatment of hyperproliferative disorders, such as cancer. This invention also relates to pharmaceutical compositions containing a compound of the present invention and pharmaceutically acceptable salts thereof.